This UW STI TM CRC application includes 4 interrelated Projects, 2 scientific Cores (Biostatistics and Laboratory), and an STI TM CRC Developmental Awards Program. The First Project, Comparative Genomics of Clinical C. trachomatis Strains (Daniel Rockey) will use the Lab Core's large specimen repository to explore linkages of chlamydial genotypes to three unique phenotypes of C. trachomatis, seeking chlamydial genes important in previously uncharacterized aspects of chlamydial biology and pathogenesis. The Second Project, Immunogenetic Correlates of Severity of Genital HSV-2 Infection (Anna Wald) will identify MHC class I and II alleles associated with HSV-2 infection severity, and determine how HLA class I-restricted CMI responses exert selective pressures on HSV-2 amino acid sequences. The Third Project, Male Microbicide Safety Acceptance & Efficacy Against STI (King Holmes) plans preclinical studies, a Phase 1 trial, and a Phase 2/3 double-blinded placebo-controlled randomized controlled trial (RCT) in Kenya of 62% ethanol in emollient gel for preventing STI acquisition by men. This promising topical microbicide is nontoxic, preferred for hand hygiene in health care settings, widely available over-the-counter for domestic use, and has been well tolerated in our NIH-funded preparatory studies in Nairobi. The Fourth Project, M. genitalium Susceptibility and Treatment (Lisa Manhart) proposes development of innovative methods to measure antimicrobial susceptibility of M. genitalium, and a double blinded, placebo-controlled RCT to determine the relationship of clinical and microbiologic outcomes to drug used, and to M. genitalium drug susceptibility. Projects will interact synergistically, and all will utilize the Biostatistics Core (James Hughes) and Laboratory Core (Walter Stamm). Sheila Lukehart proposes the STI TM CRC Developmental Awards Program.